Labile conjugation of a hydrophilic drug to PLA oligomers to modify a drugdelivery system: cephradin in a PLAGA matrix

The physical entrapment of a hydrophilic drug within degradable microsphere s is generally difficult because of poor entrapment yield and/or fast relea se, depending on the microsphere fabrication method. In order to counter th e effects of drug hydrophilicity, it is proposed to covalently attach the d rug to lactic acid oligomers, with the aim of achieving temporary hydrophob ization and slower release controlled by the separation of the drug from th e degradable link within the polymer matrix. This strategy was tested on mi crospheres of the antibiotic cephradin. As the prodrug form, the entrapment of the drug was almost quantitative. The prodrug did degrade in an aqueous medium, modelling body fluids, but cleavage did not occur at the drug-olig omer junction and drug molecules bearing two lactyl residual units were rel eased. When the prodrug is entrapped within a PLAGA matrix, no release was observed within the experimental time period. However, data suggest that co njugation via a bond more sensitive to hydrolysis than the main chain PLA e ster bonds should make the system work as desired.